1. Field of the Invention
This invention relates to β-subunit-Associated Regulator of Apoptosis, or BARA, polypeptides and nucleic acid molecules encoding the same. The invention also relates to selective binding agents, vectors, host cells, non-human transgenic animals, devices and methods for producing BARA polypeptides. The invention further relates to compositions comprising BARA nucleic acids, polypeptides, and fusions or derivatives thereof. The invention further relates to methods for treating, preventing, or ameliorating a disease, condition, or disorder comprising administering BARA or BARA compositions, as well as methods of diagnosing a pathological condition related to BARA. Still further, the invention relates to methods of modulating levels of BARA expression and methods of determining whether a compound stimulates or inhibits BARA polypeptide activity, BARA gene expression or BARA polypeptide production.
2. Background of the Related Art
The causes of benign and malignant neoplasms are complex and poorly understood. Cellular DNA can be altered or damaged in response to internal or external stimuli, which alteration or damage then acts as neoplastic perturbations in gene expression, resulting in disruption of otherwise normal cell division and proliferation. Such disruption, when resulting in unfettered cell proliferation (defined as the increase in number of cells resulting from completion of the cell cycle), can cause cancer.
Neoplasms manifest when the normal progression of and orderly relationship between cell division and cell differentiation malfunctions. Usually, cell proliferation is restricted to non-differentiated stem cells, which ordinarily differentiate and reproduce to provide a replacement for aged dying cells. In neoplasia, any cell can become uncoupled from the normal control mechanisms. The result is uncontrolled growth.
Extracellular or intracellular factors can determine whether a quiescent cell will begin to proliferate and also whether a normal proliferating cell in the G1 phase of the cell cycle will begin to cycle or will revert to quiescence. In benign and malignant neoplasms, control of proliferation is lost. Exemplary carcinogenic factors of external origin that act inside the cell include physical carcinogens such as ionizing or ultraviolet radiation and foreign substances such as cigarette smoke and asbestos. Carcinogenic substances include various chemicals, natural or man-made, which can alter or damage cellular DNA, directly or indirectly, to elicit an oncogenic event. Exemplary internal carcinogens can be biological substances such as bacteria, viruses, parasites, hormones and cytokines.
Although most mammalian tissues and organs are capable of giving rise to neoplasms, the fundamental processes resulting in tumors of diverse origins appear to be quite similar. Normal cells proliferate or reproduce in rigorous compliance with programmed guidance from parental or adjacent cells. Such unceasing, disciplined instruction ensures that each tissue maintains a size, architecture and function appropriate to the body's needs.
Neoplastic cells, in distinct contrast, become unresponsive to the usual controls of parental or adjacent cells with respect to proliferation, architecture and/or function. These neoplastic cells frequently (i) migrate from the site where they began, (ii) invade nearby tissues, and (iii) travel through the blood and lymphatic circulatory systems to form metastatic lesions at distant sites in the body. These lesions become lethal when they disrupt the normal function of other tissues or organs essential for the patient survival.
Normally, the body's tissues prevent excessive proliferation of cells by depriving them of excessive amounts of growth-stimulating factors, or by flooding the cells with antiproliferative factors derived from adjacent or parental cells which block the actions of the growth stimulating factors. However, certain cellular proteins, through their intrinsic ability to regulate a host of other genes involved in the control of cell proliferation, can reorganize and redirect a cell's normal or abnormal fate. Thus, the loss of these growth-controlling genes by deletion or mutation is a common occurrence in neoplasias (Lozano and Hulboy, 1995, Methods (San Diego) 8: 215-224.)
The majority of chemotherapeutic anti-neoplasia agents in current clinical practice disrupt major intracellular systems such as DNA synthesis and essential enzymes systems. They are toxic compounds and exert their greatest anti-neoplasia effect when employed at the maximum tolerated dose. Using these chemotherapeutic agents, toxic actions to normal tissue can greatly limit the amount that can be safely administered. To date, the most commonly utilized agents are only partially selective in their toxicity. Thus, they are damaging to both normal and neoplastic cells. Nevertheless treatment of neoplastic disease is predicated on exploiting the small differences between healthy normal cells and neoplastic cells.
There is thus a need in the art to provide anti-neoplastic and chemotherapeutic agents that are more selective and specific for tumor cells and less toxic to normal cells for treating neoplasia.